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Molecular Oncology Research Institute (MORI)

Hu, Miaofen Laboratory

Miaofen Hu, PhD, Principal Investigator, Molecular Oncology Research Institute, Tufts Medical CenterThe Miaofen Hu laboratory is studying the role of CDK6 in Notch-mediated stem cell transformation and leukemogenesis.

T-cell acute lymphoblastic leukemia (T-ALL) is a cancer of stem cells in the bone marrow that produce white blood cells in the body that normally fight infections. Despite recent advances in therapy, relapse is inevitable because the available therapies do not properly destroy enough cancer stem cells. Recent evidence indicates that more than half of all cases of T-ALL have constitutive active Notch1 receptor and abnormalities in PTEN and AKT pathway. However, blocking the activation of Notch1 fails to inhibit some T-ALL cells. The resistance to inhibition is due to the absence of PTEN, which results in constitutive activation of AKT. Uninhibited AKT activation leads to deregulated survival and proliferation independent of Notch signaling. Therefore, to improve therapeutic efficacy in human T-ALL, it is necessary either to inhibit both pathways or seek a common downstream mediator of the Notch1 and PI3K-AKT signaling pathways. We have found that cyclin-dependent kinase 6 (CDK6) is such a common mediator.

CDK6 regulates cell cycle progression and modulates differentiation of certain cells. It is predominantly expressed in hematopoietic cells and over-expressed in all cases of T-LBL/ALL. To clarify the role of CDK6 in cell cycle control and tumorigenesis, I have generated mice with targeted mutations in the Cdk6 gene. These knockin alleles generate hyperactive or inactive kinase subunits that may better mimic hyperactivation of CDK6 in tumor cells or model pharmaceutical intervention, respectively. Thus, these mouse models in hand are suitable to assess the relative contribution of Cdk6 kinase activity and non-catalytic activity to transformation and leukemogenesis. These animals therefore serve as useful tools for preclinical models of CDK6 function in cancer. 

Our laboratory studies the role of CDK6 in T-cell development and Leukemogenesis, with the aim of determining and identifying the novel therapeutic target genes regulated by CDK6 in these processes.

CDK6 regulates cell cycle progression and modulates differentiation of certain cells. It is predominantly expressed in hematopoietic cell and over-expressed in human T-ALL. To clarify the role of CDK6 in cell cycle control and tumorigenesis, I have generated mice with targeted mutations in Cdk6. These knockin alleles generate hyperactive or inactive kinase subunits that may better mimic hyperactivation of CDK6 in tumor cells or model pharmaceutical intervention, respectively.

We have found that Cdk6 and its kinase activity are required for proper development of thymocytes and for homeostasis of hematopoietic stem cells (HSCs), and for Notch-dependent proliferation, differentiation and survival. We have also found CDK6 is required for initiation of lymphomagenesis induced by active Myr-AKT. Thus, CDK6 may regulate leukemia and lymphoma formation and dissemination at multiple levels, and as such is an intriguing target for therapeutic intervention. Those evidence leads to the hypothesis that CDK6 has a role in Notch-mediated transformation.

By using retroviral transduction/in vivo bone marrow transplantation techniques and our refined Cdk6 mutant mice, we are able to determine which functional domains of Cdk6 is required for initiation and sustaining Notch-driven leukemogenesis, and to investigate how alterations of Cdk6 kinase activity may affect, at the molecular and cellular level, Notch signaling in stem cell transformation.

Figure 1. Notch signaling is essential for T cell lineage commitment, dvelopment, and lekemogenesis. CDK6 serves a common downstream mediator of the Notch1 and PI3K-AKT signaling pathways and may play a very important role in T-cell development and leukemogenesis.

Miaofen Hu, PhD, Principal Investigator, Molecular Oncology Research Institute, Tufts Medical CenterMiaofen G. Hu, MD, PhD
Principal Investigator








Li Wei is a post-doc researcher in Dr. Hu's lab in the Molecular Oncology Research Institute at Tufts Medical Center.Wei Li, PhD
Post-doc Research Fellow








Xiao Li is a post-doc researcher in Dr. Hu's lab in the Molecular Oncology Research Institute at Tufts Medical Center.XiaoLi hou, PhD
Post-doc Research Fellow

View all publications via PubMed

Note: previous name Miaofen Gu (Gu MF or Gu M) is reflected in some citations prior to 2000 instead of Miaofen G. Hu.

  1. Gu MF, Luo ZK (1990) Carbamazepine as an effective drug for the treatment of periodical mental disorder in siblings: case report. Chinese J. Neuro. Psych. Res. 168: 52-54.
  2. Schw JM, Boulis NM, Gu MF, Winickoff J, Jackson PS, Irwin N, Benowitz LI. Two factors secreted by the goldfish optic nerve induce retinal ganglion cells to regenerate axons in culture. J Neuroscience 1995; 15(8): 5514-5525.
  3. Schwalb JM, Gu MF (Co-First Author), Stuermer C, Bastmeyer M, Hu GF, Boulis N, Irwin N, Benowitz LI. Optic nerve glia secrete a low-molecular-weight factor that stimulates retinal ganglion cells to regenerate axons in goldfish. Neuroscience 1996; 72(4): 901-910.
  4. Takizawa T, Gu M, Chobanian AV, Brecher P. Effect of nitric oxide on DNA replication induced by angiotensin II in rat cardiac fibroblasts. Hypertension 1997; 30 (5): 1035-1040.
  5. Gu M, Brecher P. Nitric oxide-induced increase in p21Sdi1/Cip1/Waf1 expression during the cell cycles in aortic adventitial fibroblasts. Arterioscler Thromb Vasc Biol. 2000; 20(1): 27-34.
  6. Gu M, Lynch J and Brecher P. Nitric oxide increases p21Waf1/Cip1 expression by a cGMP-dependent pathway that includes activation of extracellular signal-regulated kinase and p70S6K.  J Biol Chem, 2000; 275: 11389-11396.
  7. Shintani S, Ohyama H, Zhang X, McBride J, Matsuo K, Tsuji K, Hu MG, Hu G-F, Kohno Y, Lerman M, Todd R, and Wong DTW. P12DOC-1 is a novel cyclin-dependent kinase 2-associated protein. Mol Cell Biol 2000; 20(17): 6300-6307.
  8. Hu MG, Hu G-F, Kim Y, Tsuji T, McBride J, Hinds PW and Wong DTW. P12DOC-1 mediates TGF-ß1 antiproliferation by negatively regulating CDK2 phosphorylation of pRB. Cancer Res. 2004; 64(2): 490-499
  9. Tsuji T, Ibaragi S, Shima K, Hu MG, Katsurano M, Sasaki A, and Hu G-F. Epithelial-Mesenchymal Transition Induced by Growth Suppressor p12CDK2-AP1 Promotes Tumor Cell Local Invasion but Suppresses Distant Colony Growth. Cancer Res. 2008; 68: (24): 10377-10386. PMCID: PMC2605670
  10. Hu MG*, Deshpande A, Enos M, Mao D, Hinds EA, Hu G-F, Chang R, Guo Z, Dose M, Mao C, Tsichlis PN, Gounari F, Hinds PW*. A Requirement for CDK6 in Thymocyte Development and Tumorigenesis. Cancer Res. 2009, 69: (3) 810-818 (*corresponding author). PMCID: PMC2636510
  11. Ibaragi S, Yoshioka N, Li S, Hu MG, Kishikawa S, and Hu G-F. Neamine Inhibits Prostate Cancer Growth by Suppressing Angiogenin-mediated Ribosomal RNA transcription. Clinical Cancer Res. 2009 Mar 10:1981-1988. PMCID: PMC2670466.
  12. Monti DM, Yu W, Pizzo E, Shima K, Hu MG, Di Malta C, Piccoli R, D'Alessio G, Hu GF. Characterization of the angiogenic activity of zebrafish ribonucleases. FEBS J. 2009 Aug; 276(15):4077-90. Epub 2009 Jun 22. PMCID: PMC2744113.
  13. Jeselsohn R, Brown NE, Klebba I, Hu MG, Kuperwasser C, Hinds PW. Lobule progenitor cells are the cellular targets of MMTV-ErbB2 tumorigenesis and require cyclin D1 activity for their maintenance. Cancer Cell. 2010 17 (1); 65-76. PMCID: PMC2818730
  14. Hu MG*, Deshpande A, Schlichting N, Hinds EA, Mao C, Dose M, Hu G-F, Van Etten RA, Gounari F, Hinds PW*. CDK6 Kinase Activity is required for Thymocyte Development (*corresponding author, Blood, 2011, 117: 6120-31).
  15. Brown NE, Jeselsohn R, Bihani T, Miaofen Hu MG, Foltopoulou P, Kuperwasser C, Hinds PW. Cyclin D1 activity regulates autophagy and senescence in the mammary epithelium (Cancer Res. 2012 Oct 29. [Epub ahead of print] PMID: 23041550 [PubMed - as supplied by publisher].
  16. Li S, Sheng JH, Hu JK, Yu WH, Kishikawa H, Hu MG, Shima K, Wu D, Xu ZP, Xin W, Sims KB, Landers JE, Brown Jr. RH, Hu GH. Ribonuclease 4 protects neuron degeneration by promoting angiogenesis, neurogenesis, and neuronal survival under stress. Angiogenesis. 2012. DOI 10.1007/s10456-012-9322-9.
  17. Luo C, Sheng J, Hu MG, Haluska FG, Cui R, Xu Z, Tsichlis PN, Hu GF, Hinds PW *. Loss of ARF sensitizes transgenic BRAFV600E mice to UV-induced melanoma via suppression of XPC. Cancer Research, Epub May 6, 2013, doi: 10.1158/0008-5472.CAN-12-4454. PMID: 23650282
  18. Li S, Hu MG, Sun Y, Yoshioka N, Ibaragi S, Sheng J, Sun G, Kishimoto K, Hu GF. Angiogenin mediates androgen-stimulated growth of prostate cancer cells and correlates with castration resistance (Mol Cancer Res. 2013 Oct;11(10):1203-14. doi: 10.1158/1541-7786.MCR-13-0072. Epub 2013 Jul 12. PMID: 23851444).
  19. Luo, C., Pietruska, J., Cui, R., Bronson, R., Hu MG, Sheng, J., Hunds, PW. Expression of oncogenic BRAFV600E in melanocytes induces Schwannian differentiation in vivo.  (Pigment Cell & Melanoma Research, 2015, Jun 2. doi: 10.1111/pcmr.12384, PMID: 26036358).
  20. Nilamani Jena, Jinghao Sheng, Jamie K Hu, Wenhui Zhu, Gene lee, Chi Luo, Elisabeth A Hinds, Nelson Brown, Amit Deshpande, Philip W Hinds, Phil Hinds, Richard A Van Etten, and Hu MG*. CDK6-mediated repression of CD25 is required for induction of T cell acute lymphoblastic leukemia by activated Notch (*corresponding author, Leukemia. 2015 Dec 28. doi: 10.1038/leu.2015.353. [Epub ahead of print], NIHMS745049).
  21. Goncalves, KA., Silberstein, L., Li, S., Severe, N., Hu, MG., Yang, HL., Scadden, DT., and Hu, GF. Angiogenin promotes hematopoietic regeneration by dichotomously regulating quiescence and expansion of stem and progenitor cells. Cell 166, 894–906, August 11, 2016. NIHMSID: NIHMS800636. PMID: 27518564 PMCID: PMC4988404